Our ongoing 20-year family-genetic study of schizophrenia and other psychotic disorders (SCZ) in the isolated population of Palau provides a valuable resource for examining the genetic and epigenetic mechanisms that govern familial transmission of SCZ. We have identified a highly promising copy number variant (CNV) that points to the possible discovery of another Disrupted-In-Schizophrenia locus. This structural variant clearly co-segregates with SCZ in a 5- generation, high-density Palauan family. Genetic, epigenetic, and functional genomic lines of evidence support its relevance for SCZ. The deletion occurs at a 9p24 site that controls histone methylation, an important epigenetic event in glutamatergic gene expression. This epigenetic locus is adjacent to the EAAC1 (excitatory-amino-acid-carrier-1) glutamate transporter gene, which plays an essential role in regulating glutamatergic neurotransmission, a well- recognized component of the pathophysiology of SCZ. The Palauan family with the 9p24 deletion is as large and as densely affected as the Scottish family that led to the discovery of the original DISC1 gene. Our preliminary studies have validated the deletion status in all affected and unaffected family members, and indicated that EAAC1 gene expression is reduced in SCZ family members with the deletion. The goals of the present application are to expand our phenotypic and genotypic assessments to include all members of the extended pedigree (N = ~75), test for co-segregation of the deletion with affection status, and conduct preliminary studies to examine the possible functional significance of the deletion in terms of EAAC1 gene expression and histone methylation levels at the 9p24 locus. Once completed, the study will provide proof of concept for a full-scale R01 study of the functional consequences of this disruption and its potential as a diagnostic biomarker for SCZ and possible target for drug development. Ultimately, this line of research may lead to improved risk prediction and treatment decisions for young high-risk individuals in the prodromal stage of SCZ when preventive intervention can be most effective. PUBLIC HEALTH RELEVANCE: Our proposed study directly addresses the need for research aimed at the prevention and treatment of the most debilitating neuropsychiatric disorders: schizophrenia, depression and bipolar disorder. Using an extraordinary 6-generation SCZ family, we aim to identify risk predictors for psychotic disorders in young people who carry a strong genetic susceptibility for disease development as they enter their adult years. The proposed developmental study represents a step toward the next generation of diagnostics and treatments that aim to identify emerging psychosis in its early prodromal stage when preventive intervention can be most effective. Because post-onset treatment has limited impact on course and outcome, the prodromal phase of psychotic disorders represent an important window of opportunity for early intervention. Preventive intervention programs for young people with prodromal symptoms have been shown to delay or even prevent illness onset and reduce the risk of the crippling functional disabilities associated with psychotic disorders.